This R21/R33 project uses functional magnetic resonance imaging (fMRI) to investigate the effects of ondansetron on neural functioning and sensory symptoms in patients with obsessive-compulsive disorder (OCD) and tic disorders (TD). Despite extensive research, 30-60% of OCD patients do not respond adequately to first-line treatments, with similarly disappointing rates in TD. OCD and TD present a treatment challenge in part because they are heterogeneous disorders characterized by clusters of symptoms likely derived from differing neural etiologies. The Research Domain Criteria (RDoC) approach seeks to address this problem by investigating transdiagnostic components of behavior that more closely align with brain circuitry. This application focuses on sensory phenomena (SP) - uncomfortable or aversive sensations preceding compulsions in OCD and tics in TD - as a critical component of both disorders with a discrete neural circuitry centered on sensory regions in the insula and somatosensory cortex. Ondansetron, a 5-HT3 receptor antagonist acting on sensory pathways, is a promising novel candidate for the modulation of neural circuits related to sensory phenomena. Ondansetron reduces sensory symptoms in non-psychiatric conditions and has been shown to decrease overall symptom severity in both OCD and TD. Our pilot data show that single 16 mg doses decrease activation of the insula and somatosensory cortex, raising the possibility that ondansetron may reduce disorder severity by directly targeting sensory circuits. Building on these promising findings, this application uses a double blind, placebo-controlled, mixed design to investigate the effects of three different doses of ondansetron on the activation of neural targets in the insula and somatosensory cortex. Milestone- driven assessment at the end of the R21 phase will provide clear support for a go/no-go decision regarding the engagement of neural targets by the drug. If target engagement is established, the R33 phase will seek to validate these neural targets in a patient sample and test the relationship between target activation and clinical symptoms. Using a double blind, placebo-controlled, parallel group design, we will measure the effects of 4 weeks of optimal dose ondansetron (determined from the R21 phase) on brain functioning and sensory phenomena in a sample of OCD and TD patients. Results from the R33 phase are expected to provide support for a second go/no-go decision regarding further clinical development of the targets and intervention. Regardless of outcomes in either phase, results from this project will increase knowledge about mechanisms of disease as well as the intervention.